Methods and compositions for treating androgenetic alopecia

ABSTRACT

A treatment method including: (a) identifying a subject in need of treatment for androgenic alopecia (AGA), and (b) orally administering a physiologically effective amount of cepharanthine (CEP) to the subject according to a dosage regimen.

RELATED APPLICATIONS

This application is a continuation in part (CIP) of U.S. Ser. No.15/164,908 filed on May 26, 2016 and having the same title and inventoras the present application which is currently pending;

which claimed benefit under 35 U.S.C. §119(e) of provisional applicationU.S. 62/166,833 filed 27, May 2015 and entitled “Methods andCompositions for Treating Androgenetic Alopecia”;

each of which is fully incorporated herein by reference.

FIELD OF THE INVENTION

The various embodiments of the invention are in the field of treatmentsfor baldness.

BACKGROUND

The alopecia types described below can affect men, women and/orchildren. Androgenetic alopecia rarely affects children.

Tinea capitis (ringworm of the scalp) is a disease caused by asuperficial fungal infection of the skin of the scalp, eyebrows, andeyelashes, with a propensity for attacking hair shafts and follicles.The disease is considered to be a form of superficial mycosis ordermatophytosis. Several other names are used when referring to thisinfection, including ringworm of the scalp and tinea tonsurans. In theUS and other regions of the world, the incidence of tinea capitis isincreasing.

The tinea capitis infection is the most common cause of hair loss inchildren. Children with tinea capitis usually have patchy hair loss withsome broken-off hairs visible just above the surface of the scalp. Thepatches of hair loss are usually round or oval, but sometimes irregular.Sometimes the hairs are broken right at the surface, and look likelittle black dots on the scalp. Sometimes gray flakes or scales areseen.

Alopecia Areata is the sudden appearance of round or oval patches ofhair loss. These patches are completely slick bald or smooth without anysigns of inflammation, scaling, or broken hairs. They appear literallyovernight, or sometimes over a few days.

Alopecia areata is thought to be caused by the body's immune systemattacking the hair follicles. At any given moment, about 1 in 1,000children has alopecia areata. About 25% of these children will also havepitting or ridging of the nails.

About 5% of children with alopecia areata will go on to develop alopeciatotalis—the loss of all the hair on the scalp. Some of these willdevelop alopecia universalis—the complete loss of body hair.

Alopecia areata is an unpredictable disease and even with completeremission it is possible for it to occur again throughout your child'slifetime.

Trauma to the hair shaft is another common cause of hair loss inchildren. Often the trauma is caused by traction (consistently worntight braids, pony-tails, etc.) or by friction (rubbing against a bed orwheelchair for example). It can also be caused by chemicals burns.

Another misunderstood cause of trauma hair loss is calledtrichotillomania, the habit of twirling or plucking the hair.Trichotillomania is thought to be an obsessive-compulsive disorder thatcan be extremely difficult to treat since the patient usually feelscompelled to pluck their hair. The hair loss is patchy, andcharacterized by broken hairs of varying length. Within the patches,hair loss is not complete. Some children with trichotillomania also havetrichophagy—the habit of eating the hair they pluck. These patients candevelop abdominal masses consisting of balls of undigested hair. As longas the hair trauma was not severe or chronic enough to cause scarring,the hair will regrow when the trauma is stopped.

Telogen effluvium is another common cause of hair loss in children. Tounderstand telogen effluvium, one must understand a hair's normal lifecycle. An individual hair follicle has a long growth phase, producingsteadily growing hair for 2 to 6 years (on average 3 years). This isfollowed by a brief transitional phase (about 3 weeks) when the hairfollicle degenerates. This in turn is followed by a resting phase (about3 months) when the hair follicle lies dormant. This last phase is calledthe telogen phase. Following the telogen phase, the growth phase beginsagain—new hairs grow and push out the old hair shafts. The whole cyclerepeats. For most people, 80% to 90% of the follicles are in the growthphase, 5% are in the brief transition phase, and 10% to 15% are in thetelogen phase. Each day about 50-150 hairs are shed and replaced by newhairs. In telogen effluvium, something happens to interrupt this normallife cycle and to throw many or all of the hairs into the telogen phase.Between 6 and 16 weeks later, partial or complete baldness appears. Manydifferent events can cause telogen effluvium, including, extremely highfevers, surgery under general anesthesia, excess vitamin A, severeprolonged emotional stress such as a death of a loved one, severeinjuries and the use of certain prescription medication such as accutanefor acne.

Androgenetic Alopecia (AGA) also known as male pattern baldness orfemale pattern baldness. It is a thinning of the hair to an almosttransparent state, in both men or women. It is thought to be ahereditary form of hair loss and is the most common type of progressivehair loss.

Alopecia—Androgenetic in Men

According to the American Hair Loss Association, androgenetic alopeciaor common male pattern baldness (MPB) accounts for most cases of hairloss in men. By the age of thirty-five two-thirds of American men willexperience some degree of appreciable hair loss, and by the age of fiftyapproximately 85% of men have significantly thinning hair. Approximatelytwenty five percent of men who suffer with male pattern baldness beginthe painful process before they reach the age of twenty-one.

Contrary to societal belief, most men who suffer from male patternbaldness are extremely unhappy with their situation and would doanything to change it. Hair loss affects every aspect of the hair losssufferer's life. It affects interpersonal relationships as well as theprofessional lives of those suffering. It is not uncommon for men tochange their career paths because of their hair loss.

Androgenic alopecia or male pattern baldness (MPB) is responsible forthe vast majority of hair loss in men. While there are many possiblereasons people lose their hair, including serious disease, reaction tocertain medications, and in rare cases extremely stressful events, mosthair loss in men can be blamed on heredity.

What male pattern baldness sufferers are actually inheriting are hairfollicles with a genetic sensitivity to Dihydrotestosterone (DHT). Hairfollicles that are sensitive to DHT begin to miniaturize, shortening thelifespan of each hair follicle affected. Eventually, these affectedfollicles stop producing cosmetically acceptable hair.

Male pattern baldness is generally characterized with the onset of areceding hairline and thinning crown. Hair in these areas including thetemples and mid-anterior scalp appear to be the most sensitive to DHT.This pattern eventually progresses into more apparent baldnessthroughout the entire top of the scalp, leaving only a rim or“horseshoe” pattern of hair remaining in the more advanced stages ofMPB. For some men even this remaining rim of hair can be affected byDHT.

Dihydrotestosterone (DHT) is a derivative or by-product of testosterone.Testosterone converts to DHT with the aid of the enzyme Type II5-alpha-reductase, which is held in the hair follicle's oil glands.While the entire genetic process of male pattern baldness is notcompletely understood, scientists do know that DHT shrinks hairfollicles, and that when DHT is suppressed, hair follicles continue tothrive. Hair follicles that are sensitive to DHT must be exposed to thehormone for a prolonged period of time in order for the affectedfollicle to complete the miniaturization process. Today, with properintervention this process can be slowed or even stopped if caught earlyenough.

According to the American Hair Loss Association The following twotreatments have been clinically proven to successfully treat hair lossin men to varying degrees.

Finasteride, Proscar/Propecia

Finasteride is the generic name for the brand name drugs Proscar andPropecia. Finasteride was originally developed by Merck as a drug totreat enlarged prostate glands (Proscar). During the trials on men withprostate problems an intriguing side effect of hair growth was observed.Since finasteride had already been approved by the FDA to treat enlargedprostates in men, Merck and Company decided to pursue the possibility ofdeveloping finasteride as the first pill to treat male pattern baldness.

On Dec. 22, 1997 the FDA approved a 1 mg dose of finasteride for thetreatment of androgenic alopecia in men (male pattern baldness).Propecia is the first drug in history to effectively treat male patternbaldness in the vast majority of men who use it.

How Propecia/Finasteride Works:

Finasteride's hair-raising success is due to its ability to specificallyinhibit Type II 5-alpha-reductace, the enzyme that converts testosteroneinto a more potent androgen dihydrotestosterone (DHT). Propecia's 1 mgdose of finasteride can effectively lower DHT levels by as much as 60%when taken daily. It is DHT that shrinks or miniaturizes the hairfollicle, which eventually leads to baldness. This 60% reduction in DHThas proven to stop the progression of hair loss in 86% of men taking thedrug during clinical trials. 65% of trial participants experienced whatwas considered a substantial increase in hair growth.

At this point, the only truly effective medically proven way to arrestthe hair loss process is to lower DHT levels. The American Hair LossAssociation recommends finasteride as the first line of attack for allmen interested in treating their male pattern baldness.

Minoxidil (Loniten)

Minoxidil (loniten) was the first drug approved by the FDA for thetreatment of male pattern baldness. For many years, minoxidill, in pillform, was widely used to treat high blood pressure. Just likefinasteride researchers discovered a very interesting side effect of thedrug. People taking the medication were growing hair in unexpectedplaces like on their cheeks and the back of their hands, some even grewhair on their foreheads.

Some enterprising researchers had the notion that applying minoxidiltopically, directly on the head, might grow hair on balding areas. Wellit did this to varying degrees depending on the extent of the hair loss.For it's time, this treatment was revolutionary.While minoxidil has been clinically proven to slow the progression ofhair loss and regrow some hair, most informed experts see it as arelatively marginally effective drug in the fight against hair loss.Since minoxidil has no effect on the hormonal process of hair loss itspositive effects are at best temporary and usually yield somewhatdisappointing long-term results.With that said, The American Hair Loss Association still recommends thedrug for those who have not responded favorably to finasteride treatmentor for those who would like to add another product to their regimen. TheAHLA does not recommend minoxidil as the first line of attack for mensuffering with male pattern baldness, but does recognize it as aneffective treatment for a small percentage of its users.In many cases minoxidil and finasteride fail. In other cases there aremedical reasons to want to avoid their use, and/or the risk of sideeffects. In such cases, an alternative therapy is needed.

Alopecia—Androgenetic in Women

According to the American Hair Loss Association:

Mistakenly thought to be a strictly male disease, women actually make upforty percent of American hair loss sufferers. Hair loss in women can beabsolutely devastating for the sufferer's self image and emotional wellbeing.

Unfortunately, society has forced women to suffer in silence. It isconsidered far more acceptable for men to go through the same hair lossprocess. Even more unfortunately, the medical community also treats theissue of women's hair loss as if it were nonexistent. Since hair lossdoesn't appear to be life threatening, most physicians pay littleattention to women's complaints about hair loss and essentially telltheir patients that “it's no big deal”, and that “you'll just have tolive with it.”

Of course what these physicians don't seem to realize is that thepsychological damage caused by hair loss and feeling unattractive can bejust as devastating as any serious disease, and in fact, can take anemotional toll that directly affects physical health.

The American Hair Loss Association recognizes that hair loss is women isa serious life altering condition that can no longer be ignored by themedical community and society as a whole.

Hair loss can be temporary or long lasting. Temporary hair loss can beeasy to fix when its cause is identified and dealt with, or difficultwhen it is not immediately clear what the cause is. Hair loss that couldpossibly have been temporary, may become long lasting as a result of anincorrect diagnosis. The potential for such misdiagnoses is perhaps themost frustrating aspect of hair loss for women.

Alopecia is the medical term for excessive or abnormal hair loss. Thereare different kinds of alopecia. What all hair loss has in common,whether it's in men or women, is that it is always a symptom ofsomething else that's gone wrong in your body. Your hair will remain onyour head where it belongs if hormone imbalance, disease, or some othercondition is not occurring. That condition may be as simple as having agene that makes you susceptible to male or female pattern baldness orone of the forms of alopecia areata, or it may be as complex as a wholehost of diseases. Fortunately, hair loss may also be a symptom of ashort-term event such as stress, pregnancy, and the taking of certainmedications. In these situations, hair will often (though not always)grow back when the event has passed. Substances, including hormones,medications, and diseases can cause a change in hair growth, sheddingphases and in their durations. When this happens, synchronous growth andshedding occur. Once the cause is dealt with, many times hairs will goback to their random pattern of growth and shedding, and the hair lossproblem stops. Unfortunately, for some women, hair loss becomes a lifelong struggle.

Dihydrotestosterone (DHT), a derivative of the male hormonetestosterone, is the enemy of hair follicles on your head. Simply put,under certain conditions DHT wants those follicles dead. This simpleaction is at the root of many kinds of hair loss, so we'll address itfirst.

Androgenetic alopecia, commonly called male or female pattern baldness,was only partially understood until the last few decades. For manyyears, scientists thought that androgenetic alopecia was caused by thepredominance of the male sex hormone, testosterone, which women alsohave in trace amounts under normal conditions. While testosterone is atthe core of the balding process. DHT is thought to be the main culprit.

Testosterone converts to DHT with the aid of the enzyme Type II 5-alphareductase, which is held in a hair follicle's oil glands. Scientists nowbelieve that it's not the amount of circulating testosterone that's theproblem but the level of DHT binding to receptors in scalp follicles.DHT shrinks hair follicles, making it impossible for healthy hair tosurvive.

The hormonal process of testosterone converting to DHT, which then harmshair follicles, happens in both men and women. Under normal conditions,women have a minute fraction of the level of testosterone that men have,but even a lower level can cause DHT-triggered hair loss in women. Andcertainly when those levels rise. DHT is even more of a problem. Thoselevels can rise and still be within what doctors consider “normal” on ablood test, even though they are high enough to cause a problem. Thelevels may not rise at all and still be a problem if you have the kindof body chemistry that is overly sensitive to even its regular levels ofchemicals, including hormones.

Since hormones operate in the healthiest manner when they are in adelicate balance, the androgens, as male hormones are called, do notneed to be raised to trigger a problem. Their counterpart femalehormones, when lowered, give an edge to these androgens, such as DHT.Such an imbalance can also cause problems, including hair loss.

Hormones are cyclical. Testosterone levels in some men drop by 10percent each decade after thirty. Women's hormone levels decline asmenopause approaches and drop sharply during menopause and beyond. Thecyclic nature of both our hair and hormones is one reason hair loss canincrease in the short term even when you are experiencing a long-termslowdown of hair loss (and a long-term increase in hair growth) while ona treatment that controls hair loss.

Androgenetic Alopecia

The majority of women with androgenic alopecia have diffuse thinning onall areas of the scalp. Men on the other hand, rarely have diffusethinning but instead have more distinct patterns of baldness. Some womenmay have a combination of two pattern types. Androgenic alopecia inwomen is due to the action of androgens, male hormones that aretypically present in only small amounts. Androgenic alopecia can becaused by a variety of factors tied to the actions of hormones,including, ovarian cysts, the taking of high androgen index birthcontrol pills, pregnancy, and menopause. Just like in men the hormoneDHT appears to be at least partially to blame for the miniaturization ofhair follicles in women suffering with female pattern baldness. Heredityplays a major factor in the disease.

Telogen Effluvium (TE)

When your body goes through something traumatic like childbirth,malnutrition, a severe infection, major surgery, or extreme stress, manyof the 90 percent or so of the hair in the anagen (growing) phase orcatagen (resting) phase can shift all at once into the shedding(telogen) phase. About 6 weeks to three month after the stressful eventis usually when the phenomenon called telogen effluvium can begin. It ispossible to lose handful of hair at time when in full-blown telogeneffluvium. For most who suffer with TE complete remission is probable aslong as severely stressful events can be avoided. For some womenhowever, telogen effluvium is a mysterious chronic disorder and canpersist for months or even years without any true understanding of anytriggering factors or stressors.

Anagen Effluvium

Anagen effluvium occurs after any insult to the hair follicle thatimpairs its mitotic or metabolic activity. This hair loss is commonlyassociated with chemotherapy. Since chemotherapy targets your body'srapidly dividing cancer cells, your body's other rapidly dividing cellssuch as hair follicles in the growing (anagen) phase, are also greatlyaffected. Soon after chemotherapy begins approximately 90 percent ormore of the hairs can fall out while still in the anagen phase.

The characteristic finding in anagen effluvium is the tapered fractureof the hair shafts. The hair shaft narrows as a result of damage to thematrix. Eventually, the shaft fractures at the site of narrowing andcauses the loss of hair.

Traction Alopecia

This condition is caused by localized trauma to the hair follicles fromtight hairstyles that pull at hair over time. If the condition isdetected early enough, the hair will regrow. Braiding, cornrows, tightponytails, and extensions are the most common styling causes.

Since the “pill” was approved by the FDA in 1960, oral contraceptiveshave become one of the most popular forms of birth control used today.

Millions of women are prescribed the pill each year in this country, butvery few are aware that oral contraceptives are a common trigger of hairloss for many who use them.

The “pill” suppresses ovulation by the combined actions of the hormonesestrogen and progestin or in some cases progestin alone. Women who arepredisposed to hormonal related hair loss or who are hypersensitive tothe hormonal changes taking place in their bodies can experience hairloss to varying degrees while on the pill or more commonly, severalweeks or months after stopping the pill.

The American Hair Loss Association recommends that all women interestedin using oral contraceptives for the prevention of conception shouldonly use low-androgen index birth control pills, and if there is astrong predisposition for genetic hair loss in your family we recommendthe use of another non-hormonal form of birth control.

The Women are in a “Catch-22” position when it comes to drug treatmentsfor androgenetic alopecia. While many drugs may work to some degree forsome women, doctors are reluctant to prescribe them, and drug companiesaren't exactly falling over themselves to test existing or new drugsspecifically for their ability to prevent and treat female patternbaldness.

Physicians are reluctant to use systemic treatment (a pill or other formof internal treatment that affects your entire system) unless they knowthat the hair loss is due to an excess of androgen in the system or asensitized “over-response” to the so-called “normal” amounts of androgenin the system. That's because these systemic treatments may lower thebody's androgen levels. Therefore, physicians often choose topicaltreatments (those that are applied directly to the scalp).

The best results from treatment happen when you begin treatment as soonas possible after the hair loss begins because prolonged androgeneticalopecia may destroy many of the hair follicles. The use ofanti-androgens after prolonged hair loss will at least help preventfurther hair loss and encourage some hair regrowth from those folliclesthat have been dormant but are still viable, Stopping treatment willresult in the hair loss resuming if the androgens aren't kept in checkin some other way. Maintaining your vitamin and mineral levels helpswhile you're on anti-androgen medications.

As always, treatments have the best chance of being effective if theyare geared to the cause of the hair loss as well as to triggering hairgrowth.

Currently there is only one FDA approved treatment for female patternhair loss.

Minoxidil 2% Topical Treatment

Minoxidil was first used in tablet form as a medicine to treat highblood pressure (an antihypertensive). It was noticed that patients beingtreated with minoxidil experienced excessive hair growth(hypertrichosis) as a side effect. Further research showed that applyinga solution of minoxidil directly to the scalp could also stimulate hairgrowth. The amount of minoxidil absorbed through the skin into thebloodstream is usually too small to cause internal side effects.

Women with diffuse androgenetic alopecia can use minoxidil and itactually seems to be more effective for women compared to men. Themakers of minoxidil recommend women only use the 2% concentration ofminoxidil and not 5%. The makers of minoxidil have not received FDAapproval for promoting 5% minoxidil or minoxidil extra strength for useby women. Many dermatologists do prescribe minoxidil 5% for women withandrogenetic alopecia if used under their supervision. Some smallclinical trials have been conducted on 5% minoxidil for androgeneticalopecia in women showing that indeed the 5% solution is significantlymore effective in both retaining and regrowing hair than the 2%solution.

In clinical studies of mostly white women aged 18-45 years with mild tomoderate degrees of hair loss, the following response to minoxidil wasreported: 19% of women reported moderate hair growth after usingminoxidil for 8 months (19% had moderate regrowth: 40% had minimalregrowth). This compares with 7% of women reporting moderate hairregrowth after using the placebo, the liquid without the activeingredient in it, for 8 months (7% had moderate regrowth, 33% hadminimal regrowth).

Propecia/Proscar

The drug finasteride inhibits the enzyme 5-alpha reductase, therebyinhibiting the production of prostate-harming, follicle killing DHT. Itwas first marketed to treat the prostate under the brand name Proscar in5 mg pills. In 1998, a 1 mg version with the brand name Propecia enteredthe market as the first pill approved by the FDA for men's hair loss. Itworks quite well for most men in both preventing hair loss andtriggering regrowth, and it may work for some women, although women mustnot take it if they are pregnant and must not get pregnant while on thedrug because of the risk of birth defects in a male fetus. Less than 2percent of men experience transient sexual side effects includingerectile and libido difficulties. In women these side effects do notoccur.

In many cases minoxidil and finasteride fail. In other cases there aremedical reasons to want to avoid their use, and/or the risk of sideeffects.

Other forms of alopecia are Cicatricial Alopecias (Scarring Alopecias)and Alopecia mucinosa

SUMMARY OF THE INVENTION

In some exemplary embodiments of the invention there is provided atreatment method including: (a) identifying a subject in need oftreatment for androgenic alopecia (AGA), and (b) orally administering aphysiologically effective amount of cepharanthine (CEP) to said subjectaccording to a dosage regimen. In some embodiments the dosing regimen isonce per day. Alternatively or additionally, in some embodiments thedosing regimen is once every other day. Alternatively or additionally,in some embodiments physiologically effective amount of CEP is 0.5 to5.0 mg/day on average. Alternatively or additionally, in someembodiments the physiologically effective amount of cepharanthine is 0.5to 2 mg/day on average. Alternatively or additionally, in someembodiments the physiologically effective amount of cepharanthine is0.75 to 1.5 mg/day on average.

In some exemplary embodiments of the invention there is provided atreatment kit comprising: (a) a plurality of oral dosage forms ofcepharanthine (CEP); and (b) packaging material comprising instructionsfor use in the treatment of androgenic alopecia (AGA) according to adosage regimen. In some embodiments the instructions include adisclaimer that CEP is not effective and/or not approved for treatmentof AGA.

Alternatively or additionally, in some embodiments each of the oraldosage forms comprises 0.5 to 5.0 mg CEP. Alternatively or additionally,in some embodiments each of the oral dosage forms comprises 0.5-1.0 mgcepharanthine. Alternatively or additionally, in some embodiments thedosing regimen is once per day or less frequent. Alternatively oradditionally, in some embodiments the dosing regimen is once every otherday. Alternatively or additionally, in some embodiments the kit islabeled as a nutritional supplements or food supplement. Alternativelyor additionally, in some embodiments the oral dosage forms are providedas capsules, pills, lozenges, dragees, buccal or sublingual formtablets, liquid form, lipid dissolved or suspended form or chewing gum.

In some exemplary embodiments of the invention there is provided amethod of manufacture comprising: (a) assembling a plurality of dosageforms of cepharanthine (CEP); and (b) packaging said plurality of dosageforms with instructions for use in the treatment of androgenic alopecia(AGA) according to a dosage regimen. In some embodiments theinstructions include a disclaimer that CEP is not effective and/or notapproved for treatment of AGA. Alternatively or additionally, in someembodiments of the dosage forms comprises 0.5 to 5.0 mg CEP.Alternatively or additionally, in some embodiments each of the dosageforms comprises 0.5-1.0 mg cepharanthine. Alternatively or additionally,in some embodiments the method includes labeling the packaging materialto indicate that the CEP is a nutritional supplements or foodsupplement. Alternatively or additionally, in some embodiments themethod includes preparing said dosage forms. According to some exemplaryembodiments of the invention the dosage forms are oral, e.g. capsules,pills, lozenges, dragees, buccal or sublingual form tablets, liquidform, lipid dissolved or suspended form or chewing gum.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS OF THE INVENTION

Cepharanthine (CEP) is a naturally occurring plant based alkaloid(isolated primarily from the stephania spp) used to treat inflammatoryconditions. CEP has successfully been used to treat a diverse range ofmedical conditions, including radiation-induced leukopenia, idiopathicthrombocytopenic purpura, alopecia areata, alopecia pityrodes, venomoussnakebites, xerostomia, sarcoidosis, refractory anemia and variouscancer-related conditions. No safety issues have been observed with CEP,and side effects are very rarely reported.

Cepharanthine has not been reported to be beneficial for androgeneticalopecia. The mechanism of hair loss in androgenetic alopecia is verydifferent from that in alopecia areata or alopecia pityrodes (which isprimarily a skin disorder).

When treating alopecia areata or alopecia pityrodes, it is commonly usedin divided doses—2-3 times a day after meals. It is generally sold as apharmaceutical product required a physician's prescription.

Experiments and Results

We have surprisingly discovered that CEP is effective in treatingandrogenetic alopecia in both males and females. It is effective whendosed once daily or even once every other day, both of which makecompliance much easier than dividing the doses into greater frequency.It is effective without regard to consumption following meals.

The description of the experiments and their results are presented inthe 4 tables below. In these experiments the subjects self-administeredCEP for at least 6 months.

TABLE 1 Androgenetic Alopecia Androgenetic Alopecia Androgenic StudyName: Males Arm 1 Males Arm 2 Alopecia Females InterventionCepharanthine 2 mg Cepharanthine 2 mg Cepharanthine 2 mg once daily onceevery other day daily Number of Subjects 40 40 30 Treated 20 20 15Controls 20 20 15 Duration of Treatment 6 months 6 months 6 monthsHamilton-Norwood Classification (Male)/ 2-5 2-5 II-2 - Frontal LudwigScale (females) Age Hair Loss First Seen 23.8 +− 5.1 26.3 +− 5.6 22.1 +−7.6 White Hair - None 21 28 17 White Hair - Few 14 11 18 White Hair -Many  5  1  3 Failed finasteride 20 18 28 Failed minoxidil 24 22 26Failed other treatments 30 35 27 Dandruff None None None GlobalPhotographic Assessement Method At 6 months, 16 of 20 At 6 months, 14 of20 At 6 months, 11 of 15 (Omnia System) active subjects active subjectsactive subjects Global photographs of midline and vortex of demonstrateddemonstrated demonstrated baseline vs 6 months were used for thisimprovement relative to improvement relative to improvement relative toevaluation. The regions assessed were the baseline - see Table 2baseline - see Table 3 baseline - see Table 4 vertex and superio-frontalregions, as well as overall head. The validated improvement scale isused in all clinical hair studies and spans from −3 = greatly decreasedto +3 greatly increased.

TABLE 2 Androgenetic Alopecia Male Arm 1 Score Placebo Active Greatlydecreased 0 0 Moderately decreased 1 0 Slightly decreased 15  1 Nochange 4 3 Slightly increased 0 8 Moderately increased 0 7 Greatlyincreased 0 1

TABLE 3 Androgenetic Alopecia Male Arm 2 Score Placebo Active Greatlydecreased 0 0 Moderately decreased 2 0 Slightly decreased 12  2 Nochange 6 4 Slightly increased 0 9 Moderately increased 0 5 Greatlyincreased 0 0

TABLE 4 Androgenetic Alopecia Females Score Placebo Active Greatlydecreased 0 0 Moderately decreased 2 0 Slightly decreased 9 1 No change3 3 Slightly increased 1 8 Moderately increased 0 2 Greatly increased 01

We also tested CEP in subjects suffering from different forms of hairloss such as congenital alopecia (atrichia congenita, hypotrichosiscongenita etc), chronic telogen effluvium and traction alopecia withoutany beneficial effects.

Since our results showed a therapeutic effect limited to androgenetic(androgenic) alopecia, this leads us to believe that CEP may possesssome influencing effect specific to androgenetic alopecia (in additionto its well known effect against inflammatory/autoimmune causedalopecia). While CEP has been reported in a single study to stimulatecortisone production (which may explain its well known effect againstinflammatory/autoimmune caused alopecia), we have found no studies ofany possible modulation of DHT as result of cepharanthine use.

In some of the successfully treated subjects, we noticed greatimprovement in pigmentation—with hair becoming darker or in a few casesbecoming completely dark after having been white pre-treatment.

Some users were not perfectly compliant, sometimes skipping their dailydoses. Since therapeutic benefit was noted in those users too, it meansthat the effective dose may be as little as 0.5 mg CEP a day. Theexpected effective dose range is from about 0.5 mg per day to about 100mg per day.

In some embodiments not less than about 0.5 mg, not less than about 1 mga day or not less than about 2 mg a day are used, in at least a singledaily dose, or in at least a single dose every other day.

In some embodiments length of treatment is at least 1 month, at least 2months, at least 3 months, at least 4 months, at least 5 months, atleast 6 months, at least 9 months, at least 12 months, at least 18months or at least 24 months.

In some embodiments, CEP is provided as the isolated pure alkaloid (witha purity level of >92%) encapsulated or prepared as a pill with wellknown inert ingredients as fillers/binders.

In some embodiments, a plant extract or plant powder is used, generallyof the stephania spp species containing cepharanthine, but where the CEPcontent is concentrated to more than its naturally occurringconcentration, and able to provide the therapeutic dose of CEP (about 1mg or about 2 mg) in at least a single dose.

In some embodiments, the CEP or CEP-containing plant extract or powderis used in a formulation that contains ingredients known to support hairsynthesis. These can include all or some of: Vitamin E, 1-taurine,Vitamin B6, Zinc salts/complexes, 1-cysteine, Vitamin B1, Vitamin B2,Vitamin B5, Vitamin B12, biotin, copper, selenium. In some embodiments,the CEP or CEP-containing plant extract or powder is used in aformulation that contains ingredients known to support hair growthand/or treat androgenetic alopecia such as serenoa repens, finasteride,minoxidil etc. In some cases synergistic activity may occur.

In some embodiments, CEP is the only active ingredient.

In some embodiments, CEP is used in oral capsule form, in oral pillform, in lozenge form, in buccal form, in sublingual form, in liquidform, in lipid dissolved or suspended form, in chewing gum form etc.

In some embodiments, treatment packs or kits are provided which includethe dosage forms containing CEP together with instructions for use. Insome embodiments, the treatment packs will include single doses and insome embodiments they may include a multiplicity of doses. In someembodiments the kits or treatment packs may include at least a 30 day,at least a 60 day, at least a 120 day, at least a 150 day, at least a180 day or at least a 360 day supply for a single user.

In some embodiments, the invention is provided as a pharmaceuticalcomposition. In some embodiments it is provided as a nutritionalsupplements or food supplement. In some embodiments, the invention willnot require a physician's prescription.

In some embodiments, especially where the product containing CEP may besold as a non-prescription item where therapeutic claims are notpermitted to be provided simultaneously with the product containing CEP,different forms may be used to disseminate details of the product andits therapeutic benefits to potential clients. This may includenewspaper advertising, media advertising, electronic, email or socialmedia based advertising and similar methods as typically used to marketproducts to consumers.

Alternatively, or additionally, features used to describe a method canbe used to characterize a composition or kit and features used todescribe a composition or kit can be used to characterize a method.

It should be further understood that the individual features describedhereinabove can be combined in all possible combinations andsub-combinations to produce additional embodiments of the invention. Theexamples given above are exemplary in nature and are not intended tolimit the scope of the invention which is defined solely by thefollowing claims.

Each recitation of an embodiment of the invention that includes aspecific feature, part, component, module or process is an explicitstatement that additional embodiments of the invention not including therecited feature, part, component, module or process exist.

Alternatively or additionally, various exemplary embodiments of theinvention exclude any specific feature, part, component, module, processor element which is not specifically disclosed herein. For example, manyembodiments of the invention do not include chromene.

The invention claimed is:
 1. A treatment method comprising: (a)identifying a subject in need of treatment for androgenic alopecia(AGA), (b) orally administering an amount of cepharanthine (CEP)effective in treating AGA to said subject according to a dosage regimen;wherein said CEP is administered without chromene.
 2. A method accordingto claim 1, wherein said dosing regimen is once per day.
 3. A methodaccording to claim 1, wherein said dosing regimen is once every otherday.
 4. A method according to claim 1, wherein said amount of CEP is 0.5to 5.0 mg/day on average.
 5. A method according to claim 1, wherein saidamount of CEP is 0.5 to 2 mg/day on average.
 6. A method according toclaim 1, wherein said amount of CEP is 0.75 to 1.5 mg/day on average. 7.A method according to claim 1, wherein said amount of CEP is 0.5 to 100mg/day on average.
 8. A method according to claim 1, wherein said CEP isprovided as a plant extract or plant powder of Stephania spp specieswith the CEP content concentrated to more than its naturalconcentration.
 9. A treatment method comprising: (a) identifying asubject in need of hair darkening, (b) orally administering an amount ofcepharanthine (CEP) effective in darkening hair to said subjectaccording to a dosage regimen.
 10. A method according to claim 9,wherein said dosing regimen is once per day.
 11. A method according toclaim 9, wherein said dosing regimen is once every other day.
 12. Amethod according to claim 9, wherein said amount of CEP is 0.5 to 5.0mg/day on average.
 13. A method according to claim 9, wherein saidamount of CEP is 0.5 to 2 mg/day on average.
 14. A method according toclaim 9, wherein said amount of CEP is 0.75 to 1.5 mg/day on average.15. A method according to claim 9, wherein said amount of CEP is 0.5 to100 mg/day on average.
 16. A treatment method comprising: orallyadministering an amount of cepharanthine (CEP) effective in treatingandrogenic alopecia (AGA) to a subject suffering from AGA according to adosage regimen without administering chromene to said subject.
 17. Amethod according to claim 1, wherein said amount of CEP is 0.5 to 5.0mg/day on average.
 18. A method according to claim 1, wherein saidamount of CEP is 0.5 to 2 mg/day on average.
 19. A method according toclaim 1, wherein said amount of CEP is 0.5 to 100 mg/day on average. 20.A method according to claim 1, wherein said CEP is provided as a plantextract or plant powder of Stephania spp species with the CEP contentconcentrated to more than its natural concentration.